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Uterine Cancer Risk Increased for Women With BRCA1 Mutations, Suggesting Benefit From Hysterectomy

NEW YORK (GenomeWeb) – Women with BRCA1 mutations are at increased risk of developing serous and serous-like endometrial cancer, according to a study appearing in JAMA Oncology today.

In a prospective cohort study, researchers led by Noah Kauff from Duke University Medical Center followed more than 1,000 women with a deleterious BRCA1 or BRCA2 mutation who had undergone risk-reducing salpingo-oophorectomy to examine their subsequent incidence of uterine cancer. As the researchers reported in their paper, women with BRCA1 mutations developed serous or serous-like endometrial cancer more often than was expected. This suggests that women seeking risk-reducing salpingo-oophorectomy might also want to consider a simultaneous hysterectomy, the researchers said.

"Given the similar surgical risks, very low mortality, acceptable costs, and potential protection against serous-like endometrial cancer, if the present results are confirmed by future studies, hysterectomy with bilateral salpingo-oophorectomy may become the preferred risk-reducing surgical approach for BRCA1+ women," Kauff and his colleagues wrote in their paper.

Risk-reducing salpingo-oophorectomy is part of the standard management of women with BRCA mutations to limit breast and ovarian cancer risk, but the role of simultaneous hysterectomy has been controversial, the researchers noted. Some studies, they said, have suggested that women with BRCA mutations remain at risk for uterine cancer, though other studies were unable to confirm that increased risk.

Kauff and his colleagues recruited 1,083 women with deleterious BRCA1 or BRCA2 mutations — or both in the case of three women — who had undergone risk-reducing salpingo-oophorectomy, but not a hysterectomy.

During the median 5.1 years of follow-up, eight women developed uterine cancer: two developed endometrioid carcinoma, one developed leiomyosarcoma, and five developed serous or serous-like endometrial carcinomas. Five of the 627 women with BRCA1 mutations and three of the 453 women with BRCA2 mutations developed uterine cancer.

To gauge whether these rates were higher than expected, the researchers compared them to expected uterine cancer incidence rates, which they gleaned from the Surveillance, Epidemiology, and End Results (SEER) database. They further adjusted that risk based on the known incidence of hysterectomies in the US population.

They used two methods to calculate cumulative uterine cancer risk, one that relied on a constant annual risk and one that assumed a constant relative risk as compared to the SEER rates.

Based on this, Kauff and his colleagues expected to observe 0.34 serous or serous-like endometrial carcinomas among BRCA+ women, but they actually observed five such cases, four of which were among women with BRCA1 mutations.

From their new data, they estimated that the risk of a BRCA1+ woman who had undergone risk-reducing salpingo-oophorectomy at the age of 45 of developing serous or serous-like carcinoma by age 70 is 2.6 percent, under the constant annual risk model, or 4.7 percent, under the relative risk model.

Tumor tissue was available for three of the five BRCA1+ women who had developed serous or serous-like carcinoma. Immunohistochemical analysis suggested that BRCA1 protein expression was lost in all three, and loss of heterozygosity analysis indicated that two of those three samples had lost the wildtype BRCA1 allele.

This 2.6 percent risk of serous or serous-like endometrial cancer is likely clinically relevant, the researchers said, given the subtype's high morbidity and mortality rates.

In a related editorial, researchers and clinicians from the University of Alabama at Birmingham said that "[p]erhaps it is time to consider that the line for risk-reducing gynecologic surgery in patients with BRCA mutations not stop at the ovaries and fallopian tubes."

They further recommended that women with BRCA1 or BRCA2 mutation who are seeking a risk-reducing salpingo-oophorectomy also be informed about the risks and benefits of a concurrent hysterectomy.

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